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    Clinical Trial Results:
    Open label multicenter Phase I/II study of the safety and efficacy of PDR001 administered to patients with advanced malignancies

    Summary
    EudraCT number
    		 2014-003929-17
    Trial protocol
    		 DE   NL   FR   ES   HU   NO   IT  
    Global end of trial date
    21 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2021
    First version publication date
    06 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CPDR001X2101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02081378
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I :To estimate the recommended Phase II dose (RP2D) and/or the maximum tolerated dose (MTD) for spartalizumab Phase ll: To estimate the anti-tumor activity of spartalizumab Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/#/
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    Taiwan: 36
    Country: Number of subjects enrolled
    Thailand: 16
    Country: Number of subjects enrolled
    Turkey: 22
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    319
    EEA total number of subjects
    160
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    202
    From 65 to 84 years
    114
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 58 patients were analyzed in Phase l and 261 patients were analyzed in Phase II of this study.

    Pre-assignment
    Screening details
    		 The study planned to analyze about 58 patients in Phase I and about 120 patients in Phase II.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1 mg/kg q2w
    Arm description
    		 Phase I Dose escalation cohort patients who took PDR001 1 mg/kg q2w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered via iv infusion over 30 minutes (up to two hours, if clinically indicated) once every 2 weeks and the starting dose was 1 mg/kg

    Arm title
    		 3 mg/kg q2w
    Arm description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q2w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered via iv infusion over 30 minutes (up to two hours, if clinically indicated) once every 2 weeks and the starting dose was 1 mg/kg

    Arm title
    		 10mg/kg q2w
    Arm description
    		 Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered via iv infusion over 30 minutes (up to two hours, if clinically indicated) once every 2 weeks and the starting dose was 1 mg/kg

    Arm title
    		 3 mg/kg q4w
    Arm description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered via iv infusion over 30 minutes (up to two hours, if clinically indicated) once every 2 weeks and the starting dose was 1 mg/kg

    Arm title
    		 5 mg/kg q4w
    Arm description
    		 Phase I Dose escalation cohort patients who took PRD001 5 mg/kg q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Spartalizumab was administered via iv infusion over 30 minutes (up to two hours, if clinically indicated) once every 2 weeks and the starting dose was 1 mg/kg

    Arm title
    		 NSCLC 400mg/q4w
    Arm description
    		 Phase II: non-small cell cancer patients who took PDR001 400 mg/q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were all treated with a flat dose of Spartalizumab 400 mg Q4W.

    Arm title
    		 Melanoma 400mg/q4w
    Arm description
    		 Phase II: Melanoma patients who took PDR001 400 mg/q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were all treated with a flat dose of Spartalizumab 400 mg Q4W.

    Arm title
    		 TNBC 400mg/q4w
    Arm description
    		 Phase II: Triple negative breast cancer (TNBC) patients who took PDR001 400 mg/q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were all treated with a flat dose of Spartalizumab 400 mg Q4W.

    Arm title
    		 NSCLC 300mg/q3w
    Arm description
    		 Phase II: non-small cell cancer patients who took PDR001 300 mg/q3w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were all treated with a flat dose of Spartalizumab 300 mg Q3W.

    Arm title
    		 ATC 400 mg/q4w
    Arm description
    		 Patients in Phase II with anaplastic thyroid cancer (ATC) who took PDR001 400 mg/q4w
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spartalizumab
    Investigational medicinal product code
    PDR001
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were all treated with a flat dose of Spartalizumab 400 mg Q4W.

    Number of subjects in period 1
    		1 mg/kg q2w 3 mg/kg q2w 10mg/kg q2w 3 mg/kg q4w 5 mg/kg q4w NSCLC 400mg/q4w Melanoma 400mg/q4w TNBC 400mg/q4w NSCLC 300mg/q3w ATC 400 mg/q4w
    Started
    16
    15
    11
    6
    10
    59
    61
    40
    59
    42
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    16
    15
    11
    6
    10
    59
    61
    40
    59
    42
         Adverse event, serious fatal
    1
    1
    1
    -
    1
    4
    8
    4
    10
    9
         Physician decision
    -
    1
    -
    -
    -
    7
    9
    2
    1
    3
         Adverse event, non-fatal
    1
    -
    -
    -
    -
    2
    3
    3
    6
    1
         Progressive Disease
    14
    11
    7
    6
    9
    43
    32
    31
    39
    27
         Subject/Guardian Decision
    -
    2
    3
    -
    -
    3
    9
    -
    3
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    1 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PDR001 1 mg/kg q2w

    Reporting group title
    3 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q2w

    Reporting group title
    10mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Reporting group title
    3 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Reporting group title
    5 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 5 mg/kg q4w

    Reporting group title
    NSCLC 400mg/q4w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 400 mg/q4w

    Reporting group title
    Melanoma 400mg/q4w
    Reporting group description
    		 Phase II: Melanoma patients who took PDR001 400 mg/q4w

    Reporting group title
    TNBC 400mg/q4w
    Reporting group description
    		 Phase II: Triple negative breast cancer (TNBC) patients who took PDR001 400 mg/q4w

    Reporting group title
    NSCLC 300mg/q3w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 300 mg/q3w

    Reporting group title
    ATC 400 mg/q4w
    Reporting group description
    		 Patients in Phase II with anaplastic thyroid cancer (ATC) who took PDR001 400 mg/q4w

    Reporting group values
    		 1 mg/kg q2w 3 mg/kg q2w 10mg/kg q2w 3 mg/kg q4w 5 mg/kg q4w NSCLC 400mg/q4w Melanoma 400mg/q4w TNBC 400mg/q4w NSCLC 300mg/q3w ATC 400 mg/q4w Total
    Number of subjects
    		 16 15 11 6 10 59 61 40 59 42 319
    Age Categorical
    Units: Participants
        < 65 years
    		 12 9 8 6 8 33 37 29 35 25 202
        ≥ 65years
    		 4 6 3 0 2 26 24 11 24 17 117
    Sex: Female, Male
    Units: Participants
        Female
    		 9 7 4 2 4 23 22 40 20 19 150
        Male
    		 7 8 7 4 6 36 39 0 39 23 169
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 10 14 8 4 8 42 37 32 50 33 238
        Black
    		 2 0 0 0 0 0 1 1 0 1 5
        Asian
    		 3 1 2 2 1 12 23 4 8 4 60
        Unknown
    		 1 0 0 0 0 5 0 2 1 4 13
        Other
    		 0 0 1 0 1 0 0 1 0 0 3
    Subject analysis sets

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PDR001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    TNBC 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with TNBC who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    TNBC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with TNBC who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    Phase 1 Part
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combination of all the patients who were enrolled in the phase one part of the study. All the patients received varying doses of the study drug, PDR001.

    Subject analysis set title
    Phase 2 Part
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combination of all the patients who were enrolled in the phase II part of the study. All the patients received varying doses of the study drug, PDR001.

    Subject analysis sets values
    		 10 mg/kg q2w 3mg/kg q4w 10 mg/kg q2w 3mg/kg q4w 10 mg/kg q2w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w 10 mg/kg q2w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w 10 mg/kg q2w 3mg/kg q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w NSCLC 300 mg/q3w NSCLC 400 mg/q4w Melanoma 400 mg/q4w NSCLC 300 mg/q3w Phase 1 Part Phase 2 Part
    Number of subjects
    11
    6
    4
    3
    11
    59
    61
    40
    59
    3
    52
    54
    33
    46
    6
    6
    9
    17
    4
    11
    19
    5
    58
    261
    Age Categorical
    Units: Participants
        < 65 years
    8
    6
        ≥ 65years
    3
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    ±
    Sex: Female, Male
    Units: Participants
        Female
    4
    2
        Male
    7
    4
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    8
    4
        Black
    0
    0
        Asian
    2
    2
        Unknown
    0
    0
        Other
    1
    0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    1 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PDR001 1 mg/kg q2w

    Reporting group title
    3 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q2w

    Reporting group title
    10mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Reporting group title
    3 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Reporting group title
    5 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 5 mg/kg q4w

    Reporting group title
    NSCLC 400mg/q4w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 400 mg/q4w

    Reporting group title
    Melanoma 400mg/q4w
    Reporting group description
    		 Phase II: Melanoma patients who took PDR001 400 mg/q4w

    Reporting group title
    TNBC 400mg/q4w
    Reporting group description
    		 Phase II: Triple negative breast cancer (TNBC) patients who took PDR001 400 mg/q4w

    Reporting group title
    NSCLC 300mg/q3w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 300 mg/q3w

    Reporting group title
    ATC 400 mg/q4w
    Reporting group description
    		 Patients in Phase II with anaplastic thyroid cancer (ATC) who took PDR001 400 mg/q4w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PDR001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    TNBC 400 mg/q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with TNBC who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    TNBC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with TNBC who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    10 mg/kg q2w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Subject analysis set title
    3mg/kg q4w
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    NSCLC 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 400 mg/q4w

    Subject analysis set title
    Melanoma 400 mg/q4w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with Melanoma who took PDR001 400 mg/q4w

    Subject analysis set title
    NSCLC 300 mg/q3w
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in Phase II with non-small cell cancer who took PDR001 300 mg/q3w

    Subject analysis set title
    Phase 1 Part
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combination of all the patients who were enrolled in the phase one part of the study. All the patients received varying doses of the study drug, PDR001.

    Subject analysis set title
    Phase 2 Part
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Combination of all the patients who were enrolled in the phase II part of the study. All the patients received varying doses of the study drug, PDR001.

    Primary: Phase l: The exposure (AUC(0-336h)) after first dose of treatment at cycle 3 (each cycle = 28 days)

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    End point title
    		 Phase l: The exposure (AUC(0-336h)) after first dose of treatment at cycle 3 (each cycle = 28 days) [1] [2]
    End point description
    Estimated the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) for PDR001. AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time.
    End point type
    Primary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 3)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis planned
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    8
    4
    4
    4
    3
    Units: day*ug/mL
        geometric mean (geometric coefficient of variation)
    270 ± 52.5
    1150 ± 51.1
    1490 ± 34.2
    3110 ± 33.1
    575 ± 21.8
    No statistical analyses for this end point

    Primary: Phase l: Incidence of dose limiting toxicities (DLTs)

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    End point title
    		 Phase l: Incidence of dose limiting toxicities (DLTs) [3] [4]
    End point description
    DLT is defined as an adverse event (AE) or abnormal laboratory value of common terminology criteria for adverse events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first cycle of treatment with PDR001 during the dose escalation part of the study for which relationship to study treatment cannot be ruled out, with some exceptions.
    End point type
    Primary
    End point timeframe
    8 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis planned
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    6
    Units: Participants
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Phase ll: Overall response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)

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    End point title
    		 Phase ll: Overall response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [5] [6]
    End point description
    ORR is the percentage of participants with a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 CR = at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required. PR = at least 2 determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required. RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Primary
    End point timeframe
    61 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis planned
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        number (confidence interval 90%)
    19.0 (9.8 to 31.8)
    15.3 (8.2 to 25.1)
    27.9 (18.6 to 38.8)
    0.0 (0.0 to 7.2)
    6.8 (2.3 to 14.8)
    No statistical analyses for this end point

    Secondary: Phase I: Serum pharmacokinetic (PK) parameter AUCs (AUC0-336h (cycle 1 only), AUCinf, AUClast AUCtau)

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    End point title
    		 Phase I: Serum pharmacokinetic (PK) parameter AUCs (AUC0-336h (cycle 1 only), AUCinf, AUClast AUCtau) [7]
    End point description
    AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time. AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1). AUCinf: The AUC from time zero to infinity (mass x time x volume-1). AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1).
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    6
    Units: day*ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle (C) 1: AUC0-336h (n=16, 13, 10, 6, 10)
    126 ± 29.5
    324 ± 24.4
    638 ± 35.3
    1270 ± 20.3
    350 ± 35.0
        C1: AUCinf (n = 1, 0,0,2,3)
    123 ± 0
    999 ± 999
    726 ± 16.0
    999 ± 999
    384 ± 9.8
        C1: AUClast
    125 ± 29.9
    353 ± 31.4
    943 ± 37.4
    1240 ± 21.6
    522 ± 39.1
        C1: AUCtau (n = 16, 13, 10, 6, 10)
    126 ± 29.5
    324 ± 24.4
    984 ± 41.9
    1270 ± 20.3
    524 ± 39.6
        C3: AUClast
    260 ± 44.8
    995 ± 60.5
    2560 ± 37.2
    2520 ± 58.4
    933 ± 21.3
        C3: AUCtau (n = 8, 4, 4, 2, 2)
    270 ± 52.5
    1150 ± 51.1
    2770 ± 26.6
    3110 ± 33.1
    1040 ± 19.1
    No statistical analyses for this end point

    Secondary: Phase I: Serum pharmacokinetic (PK) parameter Cmax

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    End point title
    		 Phase I: Serum pharmacokinetic (PK) parameter Cmax [8]
    End point description
    The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    6
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        C1 (n = 15, 15, 10, 6, 9)
    18.2 ± 26.5
    53.8 ± 23.6
    106 ± 34.2
    185 ± 18.3
    53.8 ± 29.4
        C3 (n = 10, 7, 3, 3, 2)
    29.7 ± 41.0
    112 ± 27.3
    179 ± 45.2
    312 ± 30.0
    69.7 ± 9.4
    No statistical analyses for this end point

    Secondary: Phase I: Serum pharmacokinetic (PK) parameter Tmax

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    End point title
    		 Phase I: Serum pharmacokinetic (PK) parameter Tmax [9]
    End point description
    The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    6
    Units: hour
    median (full range (min-max))
        C1 (n = 15, 15, 10, 6, 9)
    1.58 (1.38 to 2.12)
    1.57 (1.25 to 1.7)
    1.58 (1.08 to 1.67)
    1.55 (1.13 to 1.68)
    1.55 (1.5 to 1.83)
        C3 (n = 10, 7, 3, 3, 2)
    1.55 (1.45 to 1.75)
    1.55 (0.75 to 1.58)
    1.3 (0.783 to 1.82)
    1.58 (1.52 to 1.62)
    1.5 (1.5 to 1.57)
    No statistical analyses for this end point

    Secondary: Phase ll: Serum pharmacokinetic (PK) parameter AUCs (AUC336h, AUCinf, AUClast, AUCtau)

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    End point title
    		 Phase ll: Serum pharmacokinetic (PK) parameter AUCs (AUC336h, AUCinf, AUClast, AUCtau) [10]
    End point description
    AUC0-336h is the AUC from time zero to 336 hour post dose of a measurable concentration sampling time. AUClast: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1). AUCinf: The AUC from time zero to infinity (mass x time x volume-1). AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1).
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (cycle 1 & 3)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: day*ug/mL
    geometric mean (geometric coefficient of variation)
        C1: AUC0-336h (n =58, 58, 37, 54, 37)
    704 ± 28.2
    681 ± 39.4
    775 ± 31.7
    752 ± 29.3
    535 ± 29.3
        C1: AUCinf (n = 13, 8, 7, 5, 2)
    1160 ± 7.1
    1090 ± 29.6
    1080 ± 45.4
    1240 ± 25.2
    491 ± 22.7
        C1: AUClast
    865 ± 69.8
    980 ± 42.5
    1020 ± 109.9
    923 ± 76.1
    602 ± 62.2
        C1: AUCtau (n= 54, 55, 32, 48, 36)
    1070 ± 31.3
    1010 ± 39.8
    1190 ± 35.0
    1130 ± 34.9
    689 ± 40.4
        C3: AUC0-336h (n = 36, 49, 12, 40, 16)
    1290 ± 30.0
    1210 ± 36.3
    1140 ± 43.8
    1360 ± 45.7
    850 ± 50.6
        C3: AUCinf (n = 1, 1, 1, 1, 0)
    999 ± 999
    1050 ± 999
    1070 ± 999
    2340 ± 999
    135 ± 999
        C3: AUClast (n = 37, 51, 16, 44, 19)
    1600 ± 88.0
    1860 ± 39.9
    1650 ± 59.7
    1630 ± 73.4
    984 ± 78.0
        C3: AUCtau (n= 31, 44, 7, 38, 14)
    2120 ± 32.7
    1940 ± 35.5
    1790 ± 53.4
    1920 ± 44.4
    1100 ± 54.5
    No statistical analyses for this end point

    Secondary: Phase ll: Serum pharmacokinetic (PK) parameter Cmax

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    End point title
    		 Phase ll: Serum pharmacokinetic (PK) parameter Cmax [11]
    End point description
    The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration (mass x volume-1)
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        C1 (n = 52, 58, 32, 55, 35)
    100 ± 27.3
    103 ± 37.0
    111 ± 26.6
    114 ± 23.6
    79.9 ± 31.8
        C3 (n = 33, 45, 11, 39, 18)
    146 ± 22.6
    151 ± 32.0
    141 ± 33.4
    163 ± 34.7
    103 ± 36.6
    No statistical analyses for this end point

    Secondary: Phase ll: Serum pharmacokinetic (PK) parameter Tmax

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    End point title
    		 Phase ll: Serum pharmacokinetic (PK) parameter Tmax [12]
    End point description
    The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)
    End point type
    Secondary
    End point timeframe
    Predose, 1hour (h), 24h, 48h, 72h, 168h, 240h, 336h post dose (Cycle 1 & 3)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: hour
    median (full range (min-max))
        C1 (n= 52, 58, 32, 55, 35)
    1.55 (0.5 to 2.75)
    1.58 (0.55 to 2.52)
    1.58 (1.07 to 2.9)
    1.58 (1.18 to 2.15)
    1.65 (1.00 to 3.08)
        C3 (n = 33, 45, 11, 39, 18)
    1.57 (0 to 4.63)
    1.6 (0.983 to 2.08)
    1.55 (1.07 to 2.22)
    1.53 (1.42 to 1.62)
    1.58 (1.33 to 2.92)
    No statistical analyses for this end point

    Secondary: Phase I: Presence and/or concentration of anti-PDR001

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    End point title
    		 Phase I: Presence and/or concentration of anti-PDR001 [13]
    End point description
    Assessed PDR001 anti-drug anti-body (ADA) incidence in Phase I patients - the emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment was expected to be on average 1 year after the start of study treatment. For Treatment-induced ADA-positive, percentage was based on patients ADA-negative at baseline. For Treatment-boosted ADA-positive, percentage was based on patients ADA-positive at baseline.
    End point type
    Secondary
    End point timeframe
    42 months
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    11
    10
    3
    6
    Units: Participants
        Patients with ADA-negative sample at baseline
    11
    9
    9
    1
    5
        Patients with ADA-positive sample at baseline
    5
    2
    1
    2
    1
        ADA-negative
    10
    8
    8
    1
    4
        ADA-positive (i.e., ADA incidence)
    4
    2
    1
    2
    1
        Treatment-induced ADA-positive
    1
    1
    1
    0
    1
        Treatment-boosted ADA-positive
    3
    1
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Phase II: Presence and/or concentration of anti-PDR001

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    End point title
    		 Phase II: Presence and/or concentration of anti-PDR001 [14]
    End point description
    Assessed PDR001 anti-drug anti-body (ADA) incidence in Phase I patients - the emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment was expected to be on average 1 year after the start of study treatment. For Treatment -induced ADA-positive, Percentage was based on subjects ADA-negative at baseline. For Treatment-boosted ADA-positive, Percentage was based on subjects ADA-positive at baseline.
    End point type
    Secondary
    End point timeframe
    42 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    31
    52
    54
    33
    46
    Units: Participants
        Patients with ADA-negative sample at baseline
    29
    43
    48
    29
    41
        Patients with ADA-positive sample at baseline
    2
    9
    6
    4
    5
        ADA-negative
    24
    34
    46
    23
    31
        ADA-positive (i.e., ADA incidence)
    6
    11
    4
    7
    12
        Treatment-induced ADA-positive
    5
    9
    2
    6
    10
        Treatment-boosted ADA-positive
    1
    2
    2
    1
    2
    No statistical analyses for this end point

    Secondary: Phase l: Overall Response Rate (ORR) as per Investigator based on RECIST v1.1

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    End point title
    		 Phase l: Overall Response Rate (ORR) as per Investigator based on RECIST v1.1 [15]
    End point description
    ORR is the percentage of participants with a best overall response of complete response CR or partial response PR as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    6
    Units: Percentage of participants
        number (confidence interval 90%)
    0.00 (0.0 to 17.1)
    6.7 (0.3 to 27.9)
    0.0 (0.0 to 25.9)
    9.1 (0.5 to 36.4)
    0.0 (0.0 to 39.3)
    No statistical analyses for this end point

    Secondary: Phase l: Disease Control Rate (DCR) as per Investigator based on RECIST v1.1

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    End point title
    		 Phase l: Disease Control Rate (DCR) as per Investigator based on RECIST v1.1 [16]
    End point description
    DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 3 mg/kg q4w 5 mg/kg q4w 10 mg/kg q2w
    Number of subjects analysed
    16
    15
    6
    10
    11
    Units: Percentage of participants
        number (confidence interval 90%)
    56.3 (33.3 to 77.3)
    46.7 (24.4 to 70.0)
    50.0 (15.3 to 84.7)
    20.0 (3.7 to 50.7)
    27.3 (7.9 to 56.4)
    No statistical analyses for this end point

    Secondary: Phase l: Progression Free Survival (PFS) as per RECIST v1.1

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    End point title
    		 Phase l: Progression Free Survival (PFS) as per RECIST v1.1 [17]
    End point description
    PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. RECIST criteria, published in February 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group, is a Response evaluation criteria in solid tumors is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    6
    11
    Units: Percentage of participants
        median (confidence interval 90%)
    3.5 (1.8 to 6.5)
    1.9 (1.5 to 8.1)
    1.8 (1.1 to 1.8)
    2.2 (1.7 to 5.8)
    2.7 (1.1 to 3.5)
    No statistical analyses for this end point

    Secondary: Phase I: Duration of Response (DOR) as per RECIST v1.1

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    End point title
    		 Phase I: Duration of Response (DOR) as per RECIST v1.1 [18]
    End point description
    DOR: measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented. CR = at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required; PR = at least 2 determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required; PD =progression <= 12 weeks after randomization/start of treatment (and not qualifying for CR, PR or SD). SD = at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 3 mg/kg q2w 10mg/kg q2w
    Number of subjects analysed
    1
    1
    Units: months
        arithmetic mean (full range (min-max))
    261.00 (261.0 to 261.0)
    55.00 (55.0 to 55.0)
    No statistical analyses for this end point

    Secondary: Phase l only: Overall Response Rate (ORR) as per Investigator based on immune related response criteria (irRC)

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    End point title
    		 Phase l only: Overall Response Rate (ORR) as per Investigator based on immune related response criteria (irRC) [19]
    End point description
    ORR is the percentage of participants with a best overall response of complete response (CR) or partial response (PR) as per irRC. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 10mg/kg q2w 5 mg/kg q4w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    11
    10
    6
    Units: Percentage of participants
        number (confidence interval 90%)
    0.00 (0.0 to 17.1)
    6.7 (0.3 to 27.9)
    9.1 (0.5 to 36.4)
    0.0 (0.0 to 25.9)
    0.0 (0.0 to 39.3)
    No statistical analyses for this end point

    Secondary: Phase l only: Disease Control Rate (DCR) as per Investigator based on irRC

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    End point title
    		 Phase l only: Disease Control Rate (DCR) as per Investigator based on irRC [20]
    End point description
    DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 10mg/kg q2w 3 mg/kg q4w 5 mg/kg q4w
    Number of subjects analysed
    16
    15
    11
    6
    10
    Units: Percentage of participants
        number (confidence interval 90%)
    62.5 (39.1 to 82.2)
    53.3 (30.0 to 75.6)
    27.3 (7.9 to 56.4)
    50.0 (15.3 to 84.7)
    30.0 (8.7 to 60.7)
    No statistical analyses for this end point

    Secondary: Phase l only: Progression Free Survival (PFS) as per irRC

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    End point title
    		 Phase l only: Progression Free Survival (PFS) as per irRC [21]
    End point description
    PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    27 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q4w 10 mg/kg q2w 3mg/kg q4w
    Number of subjects analysed
    16
    15
    10
    11
    11
    Units: Percentage of participants
        median (confidence interval 90%)
    3.6 (1.8 to 999)
    2.7 (1.5 to 8.1)
    1.8 (1.1 to 2.8)
    2.2 (1.7 to 5.8)
    2.7 (1.1 to 5.2)
    No statistical analyses for this end point

    Secondary: Phase I: Duration of Response (DOR) as per irRC

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    End point title
    		 Phase I: Duration of Response (DOR) as per irRC [22]
    End point description
    DOR: measured from time measurement criteria are met for CR or PR (whichever status is recorded first) until first date that recurrence or PD is objectively documented CR: at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required PR: at least 1 determination of PR or better at least 4 weeks apart before progression (& not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required PD: progression <= start of treatment (& not qualifying for CR, PR or SD) SD: at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (& not qualifying for CR or PR) irRC is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 3 mg/kg q2w 10mg/kg q2w
    Number of subjects analysed
    1
    1
    Units: months
        arithmetic mean (full range (min-max))
    261.00 (261.0 to 261.0)
    55.00 (55.0 to 55.0)
    No statistical analyses for this end point

    Secondary: Phase II: Disease control rate (DCR) as per Investigator based on RECIST v1.1

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    End point title
    		 Phase II: Disease control rate (DCR) as per Investigator based on RECIST v1.1 [23]
    End point description
    DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        number (confidence interval 90%)
    31.0 (19.4 to 44.6)
    49.2 (37.8 to 60.5)
    62.3 (51.0 to 72.7)
    20.0 (10.4 to 33.2)
    35.6 (25.2 to 47.1)
    No statistical analyses for this end point

    Secondary: Phase II: Progression Free Survival as per Investigator based on RECIST v1.1

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    End point title
    		 Phase II: Progression Free Survival as per Investigator based on RECIST v1.1 [24]
    End point description
    PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. RECIST criteria, published in February 2000 by an international collaboration including the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group, is a Response evaluation criteria in solid tumors is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        median (confidence interval 90%)
    1.7 (1.4 to 1.9)
    2.7 (1.9 to 5.4)
    4.7 (3.5 to 5.6)
    1.7 (1.7 to 1.8)
    1.9 (1.8 to 2.1)
    No statistical analyses for this end point

    Secondary: Phase II: Duration of response (DOR) as per Investigator based on RECIST v1.1

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    End point title
    		 Phase II: Duration of response (DOR) as per Investigator based on RECIST v1.1 [25]
    End point description
    DOR is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. PD = progression <= start of treatment (and not qualifying for CR, PR or SD). SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). RECIST criteria is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    8
    9
    17
    4
    Units: months
        median (confidence interval 90%)
    22.8 (5.7 to 999)
    5.6 (3.9 to 16.6)
    32.0 (11.1 to 999)
    10.9 (3.7 to 999)
    No statistical analyses for this end point

    Secondary: Phase II: Overall response rate (ORR) as per Investigator based on irRC

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    End point title
    		 Phase II: Overall response rate (ORR) as per Investigator based on irRC [26]
    End point description
    ORR is the percentage of participants with a best overall response CR or PR as per irRC. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        number (confidence interval 90%)
    23.8 (13.5 to 37.0)
    18.6 (10.8 to 29.0)
    31.1 (21.5 to 42.3)
    0.0 (0.0 to 7.2)
    8.5 (3.4 to 17.0)
    No statistical analyses for this end point

    Secondary: Phase II: Disease Control rate (DCR) as per Investigator based on irRC

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    End point title
    		 Phase II: Disease Control rate (DCR) as per Investigator based on irRC [27]
    End point description
    DCR is the percentage of patients with a best overall response of CR or PR or stable disease (SD). CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) where confirmation required or one determination of PR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment (and not qualifying for CR or PR). The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        number (confidence interval 90%)
    35.7 (23.5 to 49.5)
    55.9 (44.4 to 67.0)
    67.2 (56.0 to 77.1)
    22.5 (12.3 to 36.0)
    39.0 (28.3 to 50.5)
    No statistical analyses for this end point

    Secondary: Phase II: Progression Free Survival (PFS) per irRC

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    End point title
    		 Phase II: Progression Free Survival (PFS) per irRC [28]
    End point description
    PFS is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. PFS is per Kaplan-Meier estimates. The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug.
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w TNBC 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    42
    59
    61
    40
    59
    Units: Percentage of participants
        median (confidence interval 90%)
    1.7 (1.4 to 1.9)
    3.7 (2.6 to 7.1)
    5.4 (3.7 to 6.5)
    1.8 (1.7 to 1.8)
    2.0 (1.8 to 2.2)
    No statistical analyses for this end point

    Secondary: Phase II: Duration of response (DOR) per irRC

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    End point title
    		 Phase II: Duration of response (DOR) per irRC [29]
    End point description
    DOR: measured from time measurement criteria are met for CR or PR (whichever status is recorded first) until first date that recurrence or PD is objectively documented CR: at least 2 determinations of CR at least 4 weeks apart before progression where confirmation required or 1 determination of CR prior to progression where confirmation not required PR: at least 1 determination of PR or better at least 4 weeks apart before progression (& not qualifying for a CR) where confirmation required or 1 determination of PR prior to progression where confirmation not required PD: progression <= start of treatment (& not qualifying for CR, PR or SD) SD: at least 1 SD assessment (or better) > 6 weeks after randomization/start of treatment (& not qualifying for CR or PR) irRC is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug
    End point type
    Secondary
    End point timeframe
    61 months
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis planned
    End point values
    		 ATC 400 mg/q4w NSCLC 400 mg/q4w Melanoma 400 mg/q4w NSCLC 300 mg/q3w
    Number of subjects analysed
    10
    11
    19
    5
    Units: months
        median (confidence interval 90%)
    22.1 (3.8 to 999)
    5.6 (5.3 to 16.6)
    32.0 (15.6 to 999)
    10.9 (3.7 to 999)
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    On treatment deaths were collected from the start of treatment up tp 30 days after study drug discontinuation, for a maximum duration of 114.3 weeks for Phase I part (treatment duration ranged from 2 to 110.3 weeks) and a maximum duration of 194.9 weeks for Phase II part (treatment duration ranged from 0.6 tp 190.9 weeks). Deaths post treatment survival follow up were collected after the on-treatment period up to approx. 63 months.
    End point type
    Post-hoc
    End point timeframe
    On treatment deaths: approx. 114.3 weeks (Phase I) & 194.9 weeks (phase II), all deaths: approx. 63 months
    End point values
    		 Phase 1 Part Phase 2 Part
    Number of subjects analysed
    58
    261
    Units: Participants
        On-treatment deaths
    8
    35
        Total deaths
    37
    177
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment deaths were collected from first patient first treatment up to 30 days after study drug discontinuation, for a maximum duration of 114.3 weeks for the Part I phase and for a maximum duration of 194.9 weeks for the Phase II part.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    1 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PDR001 1 mg/kg q2w

    Reporting group title
    3 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q2w

    Reporting group title
    10 mg/kg q2w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 10 mg/kg q2w

    Reporting group title
    All Phase I q2w
    Reporting group description
    		 Phase I dose Cohorts - All patients in Phase I who took PDR001 q2w

    Reporting group title
    3 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 3 mg/kg q4w

    Reporting group title
    5 mg/kg q4w
    Reporting group description
    		 Phase I Dose escalation cohort patients who took PRD001 5 mg/kg q4w

    Reporting group title
    All phase I q4w
    Reporting group description
    		 Phase I dose Cohorts - All patients in Phase I who took PDR001 q4w

    Reporting group title
    All phase I patients
    Reporting group description
    		 All patients in Phase I regardless of how they took PDR001

    Reporting group title
    NSCLC 400mg/q4w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 400 mg/q4w

    Reporting group title
    Melanoma 400mg/q4w
    Reporting group description
    		 Phase II: Melanoma patients who took PDR001 400 mg/q4w

    Reporting group title
    TNBC 400mg/q4w
    Reporting group description
    		 Phase II: Triple negative breast cancer (TNBC) patients who took PDR001 400 mg/q4w

    Reporting group title
    NSCLC 300mg/q3w
    Reporting group description
    		 Phase II: non-small cell cancer patients who took PDR001 300 mg/q3w

    Reporting group title
    ATC 400 mg/q4w
    Reporting group description
    		 Patients in Phase II with anaplastic thyroid cancer (ATC) who took PDR001 400 mg/q4w

    Reporting group title
    All phase II patients
    Reporting group description
    		 All patients in Phase II regardless of how they took PDR001

    Serious adverse events
    		 1 mg/kg q2w 3 mg/kg q2w 10 mg/kg q2w All Phase I q2w 3 mg/kg q4w 5 mg/kg q4w All phase I q4w All phase I patients NSCLC 400mg/q4w Melanoma 400mg/q4w TNBC 400mg/q4w NSCLC 300mg/q3w ATC 400 mg/q4w All phase II patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 16 (56.25%)
    7 / 15 (46.67%)
    4 / 11 (36.36%)
    20 / 42 (47.62%)
    2 / 6 (33.33%)
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    24 / 58 (41.38%)
    27 / 59 (45.76%)
    22 / 61 (36.07%)
    18 / 40 (45.00%)
    37 / 59 (62.71%)
    22 / 42 (52.38%)
    126 / 261 (48.28%)
         number of deaths (all causes)
    2
    2
    1
    5
    1
    2
    3
    8
    4
    4
    4
    12
    11
    35
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Metastases to central nervous system
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour inflammation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complication of device insertion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    3 / 59 (5.08%)
    1 / 61 (1.64%)
    3 / 40 (7.50%)
    7 / 59 (11.86%)
    2 / 42 (4.76%)
    16 / 261 (6.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 3
    0 / 1
    2 / 4
    0 / 7
    0 / 2
    2 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 5
    0 / 1
    0 / 7
    Haemoptysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    5 / 40 (12.50%)
    2 / 59 (3.39%)
    2 / 42 (4.76%)
    11 / 261 (4.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    0 / 1
    0 / 5
    0 / 2
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    2 / 59 (3.39%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    2 / 59 (3.39%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Tracheal stenosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    3 / 59 (5.08%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    4 / 261 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    Cardiac tamponade
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    3 / 59 (5.08%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    2 / 42 (4.76%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Gastric ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    1 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    4 / 59 (6.78%)
    0 / 42 (0.00%)
    6 / 261 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    2 / 42 (4.76%)
    4 / 261 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    3 / 59 (5.08%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    5 / 59 (8.47%)
    3 / 42 (7.14%)
    11 / 261 (4.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 5
    0 / 0
    0 / 0
    1 / 6
    0 / 3
    1 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Postoperative wound infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    2 / 42 (4.76%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypercalcaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1 mg/kg q2w 3 mg/kg q2w 10 mg/kg q2w All Phase I q2w 3 mg/kg q4w 5 mg/kg q4w All phase I q4w All phase I patients NSCLC 400mg/q4w Melanoma 400mg/q4w TNBC 400mg/q4w NSCLC 300mg/q3w ATC 400 mg/q4w All phase II patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    15 / 15 (100.00%)
    11 / 11 (100.00%)
    42 / 42 (100.00%)
    6 / 6 (100.00%)
    10 / 10 (100.00%)
    16 / 16 (100.00%)
    58 / 58 (100.00%)
    54 / 59 (91.53%)
    55 / 61 (90.16%)
    37 / 40 (92.50%)
    56 / 59 (94.92%)
    39 / 42 (92.86%)
    241 / 261 (92.34%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    5 / 59 (8.47%)
    0 / 42 (0.00%)
    8 / 261 (3.07%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    0
    5
    0
    8
    Tumour haemorrhage
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    2
    0
    1
    0
    0
    1
    2
    Tumour pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    6 / 40 (15.00%)
    0 / 59 (0.00%)
    3 / 42 (7.14%)
    10 / 261 (3.83%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    6
    0
    4
    11
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    2
    0
    0
    2
    Hot flush
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    1
    2
    0
    3
    Hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    1
    0
    0
    1
    1
    3
    Lymphoedema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    1
    1
    0
    1
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    12 / 59 (20.34%)
    8 / 61 (13.11%)
    4 / 40 (10.00%)
    12 / 59 (20.34%)
    8 / 42 (19.05%)
    44 / 261 (16.86%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    12
    11
    4
    17
    8
    52
    Chills
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    4 / 58 (6.90%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    2 / 40 (5.00%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    2
    1
    1
    4
    0
    0
    0
    4
    0
    1
    2
    2
    1
    6
    Face oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    1
    2
    1
    0
    0
    0
    1
    2
    Fatigue
         subjects affected / exposed
    10 / 16 (62.50%)
    3 / 15 (20.00%)
    2 / 11 (18.18%)
    15 / 42 (35.71%)
    2 / 6 (33.33%)
    5 / 10 (50.00%)
    7 / 16 (43.75%)
    22 / 58 (37.93%)
    11 / 59 (18.64%)
    12 / 61 (19.67%)
    13 / 40 (32.50%)
    12 / 59 (20.34%)
    6 / 42 (14.29%)
    54 / 261 (20.69%)
         occurrences all number
    10
    4
    2
    16
    2
    6
    8
    24
    12
    12
    14
    12
    7
    57
    Inflammation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    1
    1
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    1
    2
    Malaise
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    4 / 59 (6.78%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    4
    0
    0
    0
    0
    4
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    5 / 58 (8.62%)
    2 / 59 (3.39%)
    3 / 61 (4.92%)
    2 / 40 (5.00%)
    8 / 59 (13.56%)
    0 / 42 (0.00%)
    15 / 261 (5.75%)
         occurrences all number
    1
    2
    1
    4
    0
    1
    1
    5
    3
    3
    2
    14
    0
    22
    Oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    2 / 11 (18.18%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    6 / 58 (10.34%)
    5 / 59 (8.47%)
    3 / 61 (4.92%)
    5 / 40 (12.50%)
    4 / 59 (6.78%)
    7 / 42 (16.67%)
    24 / 261 (9.20%)
         occurrences all number
    1
    3
    2
    6
    0
    2
    2
    8
    5
    4
    7
    4
    8
    28
    Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    5 / 261 (1.92%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    1
    0
    2
    1
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    3
    0
    0
    0
    3
    Pyrexia
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    6 / 58 (10.34%)
    9 / 59 (15.25%)
    9 / 61 (14.75%)
    3 / 40 (7.50%)
    11 / 59 (18.64%)
    9 / 42 (21.43%)
    41 / 261 (15.71%)
         occurrences all number
    4
    2
    1
    7
    0
    1
    1
    8
    13
    11
    3
    26
    13
    66
    Swelling face
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    0
    2
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    0
    2
    Vulvovaginal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 16 (18.75%)
    4 / 15 (26.67%)
    0 / 11 (0.00%)
    7 / 42 (16.67%)
    0 / 6 (0.00%)
    3 / 10 (30.00%)
    3 / 16 (18.75%)
    10 / 58 (17.24%)
    13 / 59 (22.03%)
    8 / 61 (13.11%)
    10 / 40 (25.00%)
    20 / 59 (33.90%)
    6 / 42 (14.29%)
    57 / 261 (21.84%)
         occurrences all number
    5
    5
    0
    10
    0
    3
    3
    13
    18
    10
    10
    22
    6
    66
    Dyspnoea
         subjects affected / exposed
    5 / 16 (31.25%)
    7 / 15 (46.67%)
    2 / 11 (18.18%)
    14 / 42 (33.33%)
    0 / 6 (0.00%)
    4 / 10 (40.00%)
    4 / 16 (25.00%)
    18 / 58 (31.03%)
    17 / 59 (28.81%)
    1 / 61 (1.64%)
    10 / 40 (25.00%)
    18 / 59 (30.51%)
    9 / 42 (21.43%)
    55 / 261 (21.07%)
         occurrences all number
    9
    9
    3
    21
    0
    4
    4
    25
    17
    2
    10
    18
    10
    57
    Dyspnoea exertional
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    2
    0
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    2 / 59 (3.39%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    4 / 42 (9.52%)
    9 / 261 (3.45%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    2
    1
    0
    3
    6
    12
    Hiccups
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    1
    0
    0
    1
    2
    Hypoxia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    4 / 261 (1.53%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    1
    0
    1
    1
    1
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    3 / 59 (5.08%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    4 / 42 (9.52%)
    9 / 261 (3.45%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    3
    0
    1
    1
    4
    9
    Pleural effusion
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    7 / 58 (12.07%)
    3 / 59 (5.08%)
    1 / 61 (1.64%)
    4 / 40 (10.00%)
    3 / 59 (5.08%)
    1 / 42 (2.38%)
    12 / 261 (4.60%)
         occurrences all number
    4
    1
    1
    6
    0
    4
    4
    10
    3
    1
    4
    5
    1
    14
    Pneumonitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    3 / 59 (5.08%)
    3 / 61 (4.92%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    6 / 261 (2.30%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    4
    4
    0
    0
    0
    8
    Productive cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    6 / 59 (10.17%)
    1 / 61 (1.64%)
    3 / 40 (7.50%)
    2 / 59 (3.39%)
    3 / 42 (7.14%)
    15 / 261 (5.75%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    2
    6
    1
    3
    4
    3
    17
    Respiratory tract congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    2 / 42 (4.76%)
    4 / 261 (1.53%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    1
    1
    2
    4
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    3 / 59 (5.08%)
    2 / 42 (4.76%)
    8 / 261 (3.07%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    3
    2
    8
    Confusional state
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    0
    1
    0
    0
    2
    Depression
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    2 / 59 (3.39%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    2 / 42 (4.76%)
    7 / 261 (2.68%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    1
    2
    2
    0
    1
    2
    2
    7
    Hallucination
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    1
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 6 (16.67%)
    3 / 10 (30.00%)
    4 / 16 (25.00%)
    5 / 58 (8.62%)
    2 / 59 (3.39%)
    6 / 61 (9.84%)
    4 / 40 (10.00%)
    5 / 59 (8.47%)
    2 / 42 (4.76%)
    19 / 261 (7.28%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    4
    5
    2
    6
    4
    6
    2
    20
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    2 / 59 (3.39%)
    7 / 61 (11.48%)
    5 / 40 (12.50%)
    5 / 59 (8.47%)
    3 / 42 (7.14%)
    22 / 261 (8.43%)
         occurrences all number
    1
    0
    2
    3
    0
    1
    1
    4
    2
    7
    7
    7
    4
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    2 / 11 (18.18%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    6 / 58 (10.34%)
    3 / 59 (5.08%)
    7 / 61 (11.48%)
    8 / 40 (20.00%)
    5 / 59 (8.47%)
    2 / 42 (4.76%)
    25 / 261 (9.58%)
         occurrences all number
    2
    2
    2
    6
    0
    1
    1
    7
    3
    7
    10
    6
    2
    28
    Bacterial test positive
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    5 / 58 (8.62%)
    2 / 59 (3.39%)
    2 / 61 (3.28%)
    6 / 40 (15.00%)
    3 / 59 (5.08%)
    1 / 42 (2.38%)
    14 / 261 (5.36%)
         occurrences all number
    4
    3
    0
    7
    0
    0
    0
    7
    2
    2
    6
    3
    1
    14
    Blood bilirubin increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    3 / 59 (5.08%)
    1 / 42 (2.38%)
    5 / 261 (1.92%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    0
    4
    0
    4
    1
    9
    Blood creatinine decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    1 / 40 (2.50%)
    4 / 59 (6.78%)
    0 / 42 (0.00%)
    10 / 261 (3.83%)
         occurrences all number
    2
    1
    0
    3
    0
    1
    1
    4
    1
    9
    1
    8
    0
    19
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    1
    0
    1
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    2 / 40 (5.00%)
    3 / 59 (5.08%)
    1 / 42 (2.38%)
    8 / 261 (3.07%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    1
    2
    3
    1
    8
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    5 / 261 (1.92%)
         occurrences all number
    0
    0
    3
    3
    0
    0
    0
    3
    0
    3
    2
    0
    0
    5
    Transaminases increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    1
    1
    3
    0
    0
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    7 / 42 (16.67%)
    1 / 6 (16.67%)
    3 / 10 (30.00%)
    4 / 16 (25.00%)
    11 / 58 (18.97%)
    6 / 59 (10.17%)
    5 / 61 (8.20%)
    2 / 40 (5.00%)
    9 / 59 (15.25%)
    2 / 42 (4.76%)
    24 / 261 (9.20%)
         occurrences all number
    4
    2
    1
    7
    1
    3
    4
    11
    6
    6
    2
    10
    2
    26
    Weight increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    0
    2
    0
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    3 / 61 (4.92%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    2
    0
    5
    0
    2
    0
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    0
    1
    1
    0
    0
    2
    Joint dislocation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Ligament rupture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    3
    1
    0
    4
    1
    0
    1
    5
    1
    1
    0
    0
    0
    2
    Wound complication
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    1
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    1
    1
    1
    2
    1
    6
    Tachycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    5 / 261 (1.92%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    2
    1
    2
    0
    1
    1
    5
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    3 / 59 (5.08%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    3
    Aphasia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    4 / 16 (25.00%)
    6 / 15 (40.00%)
    0 / 11 (0.00%)
    10 / 42 (23.81%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    10 / 58 (17.24%)
    1 / 59 (1.69%)
    5 / 61 (8.20%)
    4 / 40 (10.00%)
    10 / 59 (16.95%)
    3 / 42 (7.14%)
    23 / 261 (8.81%)
         occurrences all number
    5
    8
    0
    13
    0
    0
    0
    13
    1
    5
    4
    10
    4
    24
    Dysarthria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    0
    2
    0
    2
    0
    1
    1
    3
    1
    0
    0
    1
    0
    2
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 15 (26.67%)
    1 / 11 (9.09%)
    6 / 42 (14.29%)
    1 / 6 (16.67%)
    3 / 10 (30.00%)
    4 / 16 (25.00%)
    10 / 58 (17.24%)
    4 / 59 (6.78%)
    4 / 61 (6.56%)
    2 / 40 (5.00%)
    7 / 59 (11.86%)
    5 / 42 (11.90%)
    22 / 261 (8.43%)
         occurrences all number
    1
    4
    1
    6
    2
    3
    5
    11
    5
    4
    2
    8
    5
    24
    Hypoaesthesia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences all number
    1
    1
    0
    2
    1
    0
    1
    3
    1
    1
    1
    0
    0
    3
    Lethargy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    1
    2
    0
    0
    1
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    4 / 59 (6.78%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    1
    0
    0
    4
    1
    6
    Paralysis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    1
    0
    0
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    1
    1
    0
    0
    1
    3
    Presyncope
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    1
    0
    0
    2
    0
    3
    Taste disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 16 (31.25%)
    7 / 15 (46.67%)
    2 / 11 (18.18%)
    14 / 42 (33.33%)
    1 / 6 (16.67%)
    3 / 10 (30.00%)
    4 / 16 (25.00%)
    18 / 58 (31.03%)
    16 / 59 (27.12%)
    13 / 61 (21.31%)
    6 / 40 (15.00%)
    8 / 59 (13.56%)
    11 / 42 (26.19%)
    54 / 261 (20.69%)
         occurrences all number
    10
    11
    3
    24
    1
    3
    4
    28
    18
    17
    7
    10
    13
    65
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    1
    1
    Leukopenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    2
    0
    0
    0
    2
    Lymph node pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    3 / 61 (4.92%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    7 / 261 (2.68%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    3
    1
    1
    1
    7
    Neutropenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    1
    1
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    0
    3
    0
    3
    0
    0
    0
    3
    0
    3
    1
    3
    1
    8
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    Otorrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    1
    3
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Photopsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    0
    0
    2
    0
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    4 / 261 (1.53%)
         occurrences all number
    1
    1
    1
    3
    0
    2
    2
    5
    1
    1
    1
    0
    1
    4
    Abdominal pain
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 15 (13.33%)
    2 / 11 (18.18%)
    7 / 42 (16.67%)
    2 / 6 (33.33%)
    3 / 10 (30.00%)
    5 / 16 (31.25%)
    12 / 58 (20.69%)
    3 / 59 (5.08%)
    2 / 61 (3.28%)
    5 / 40 (12.50%)
    5 / 59 (8.47%)
    3 / 42 (7.14%)
    18 / 261 (6.90%)
         occurrences all number
    3
    2
    2
    7
    5
    4
    9
    16
    3
    2
    5
    5
    3
    18
    Abdominal pain lower
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    1
    1
    1
    3
    0
    0
    0
    3
    1
    1
    0
    2
    0
    4
    Ascites
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    2 / 6 (33.33%)
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    5 / 58 (8.62%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    2 / 40 (5.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    1
    0
    0
    1
    2
    2
    4
    5
    0
    0
    2
    0
    0
    2
    Autoimmune colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    5 / 16 (31.25%)
    5 / 15 (33.33%)
    0 / 11 (0.00%)
    10 / 42 (23.81%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
    2 / 16 (12.50%)
    12 / 58 (20.69%)
    8 / 59 (13.56%)
    7 / 61 (11.48%)
    9 / 40 (22.50%)
    9 / 59 (15.25%)
    5 / 42 (11.90%)
    38 / 261 (14.56%)
         occurrences all number
    5
    8
    0
    13
    2
    0
    2
    15
    10
    7
    9
    9
    5
    40
    Diarrhoea
         subjects affected / exposed
    7 / 16 (43.75%)
    6 / 15 (40.00%)
    1 / 11 (9.09%)
    14 / 42 (33.33%)
    0 / 6 (0.00%)
    3 / 10 (30.00%)
    3 / 16 (18.75%)
    17 / 58 (29.31%)
    8 / 59 (13.56%)
    8 / 61 (13.11%)
    1 / 40 (2.50%)
    12 / 59 (20.34%)
    8 / 42 (19.05%)
    37 / 261 (14.18%)
         occurrences all number
    9
    6
    5
    20
    0
    5
    5
    25
    17
    11
    1
    27
    13
    69
    Dry mouth
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    5 / 42 (11.90%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    6 / 58 (10.34%)
    3 / 59 (5.08%)
    3 / 61 (4.92%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    3 / 42 (7.14%)
    10 / 261 (3.83%)
         occurrences all number
    3
    1
    1
    5
    0
    1
    1
    6
    3
    3
    1
    0
    3
    10
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    2 / 59 (3.39%)
    3 / 61 (4.92%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    7 / 261 (2.68%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    1
    2
    2
    3
    0
    1
    1
    7
    Dysphagia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    3 / 59 (5.08%)
    5 / 42 (11.90%)
    8 / 261 (3.07%)
         occurrences all number
    1
    2
    0
    3
    0
    0
    0
    3
    0
    0
    0
    3
    5
    8
    Flatulence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    2
    1
    0
    3
    0
    0
    0
    3
    1
    1
    0
    0
    0
    2
    Mouth haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    1
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    7 / 16 (43.75%)
    4 / 15 (26.67%)
    3 / 11 (27.27%)
    14 / 42 (33.33%)
    3 / 6 (50.00%)
    4 / 10 (40.00%)
    7 / 16 (43.75%)
    21 / 58 (36.21%)
    9 / 59 (15.25%)
    6 / 61 (9.84%)
    13 / 40 (32.50%)
    15 / 59 (25.42%)
    2 / 42 (4.76%)
    45 / 261 (17.24%)
         occurrences all number
    8
    4
    4
    16
    4
    4
    8
    24
    10
    6
    14
    17
    2
    49
    Pancreatic duct dilatation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    2 / 40 (5.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    2
    2
    1
    1
    7
    Toothache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    1
    0
    1
    Vomiting
         subjects affected / exposed
    6 / 16 (37.50%)
    1 / 15 (6.67%)
    3 / 11 (27.27%)
    10 / 42 (23.81%)
    2 / 6 (33.33%)
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    14 / 58 (24.14%)
    8 / 59 (13.56%)
    8 / 61 (13.11%)
    5 / 40 (12.50%)
    8 / 59 (13.56%)
    3 / 42 (7.14%)
    32 / 261 (12.26%)
         occurrences all number
    6
    2
    3
    11
    4
    2
    6
    17
    10
    9
    5
    14
    4
    42
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    1
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Cold sweat
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    2
    1
    1
    0
    4
    Hyperhidrosis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    1
    1
    1
    1
    0
    4
    Lichen planus
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    4 / 261 (1.53%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    1
    0
    1
    1
    1
    4
    Pain of skin
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 16 (18.75%)
    5 / 15 (33.33%)
    1 / 11 (9.09%)
    9 / 42 (21.43%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    9 / 58 (15.52%)
    7 / 59 (11.86%)
    8 / 61 (13.11%)
    4 / 40 (10.00%)
    3 / 59 (5.08%)
    5 / 42 (11.90%)
    27 / 261 (10.34%)
         occurrences all number
    4
    5
    1
    10
    0
    0
    0
    10
    7
    10
    4
    4
    6
    31
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    5 / 59 (8.47%)
    6 / 61 (9.84%)
    3 / 40 (7.50%)
    3 / 59 (5.08%)
    3 / 42 (7.14%)
    20 / 261 (7.66%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    5
    7
    3
    5
    3
    23
    Rash erythematous
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    2 / 59 (3.39%)
    3 / 61 (4.92%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    7 / 261 (2.68%)
         occurrences all number
    1
    2
    0
    3
    0
    0
    0
    3
    2
    5
    0
    2
    1
    10
    Skin ulcer
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Vitiligo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    0 / 59 (0.00%)
    10 / 61 (16.39%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    11 / 261 (4.21%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    10
    0
    0
    1
    11
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    1
    1
    3
    Azotaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    5 / 261 (1.92%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    1
    5
    1
    8
    Haematuria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    1
    2
    0
    1
    0
    0
    0
    1
    Hydronephrosis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    2
    0
    0
    0
    1
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    1
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    5 / 59 (8.47%)
    4 / 61 (6.56%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    1 / 42 (2.38%)
    13 / 261 (4.98%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    4
    1
    2
    1
    13
    Hypothyroidism
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 15 (20.00%)
    1 / 11 (9.09%)
    7 / 42 (16.67%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
    2 / 16 (12.50%)
    9 / 58 (15.52%)
    4 / 59 (6.78%)
    5 / 61 (8.20%)
    3 / 40 (7.50%)
    3 / 59 (5.08%)
    2 / 42 (4.76%)
    17 / 261 (6.51%)
         occurrences all number
    3
    3
    1
    7
    0
    2
    2
    9
    4
    6
    3
    3
    2
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    1 / 6 (16.67%)
    2 / 10 (20.00%)
    3 / 16 (18.75%)
    7 / 58 (12.07%)
    8 / 59 (13.56%)
    7 / 61 (11.48%)
    0 / 40 (0.00%)
    6 / 59 (10.17%)
    6 / 42 (14.29%)
    27 / 261 (10.34%)
         occurrences all number
    0
    3
    1
    4
    1
    2
    3
    7
    9
    8
    0
    6
    6
    29
    Back pain
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    4 / 42 (9.52%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    5 / 58 (8.62%)
    8 / 59 (13.56%)
    1 / 61 (1.64%)
    3 / 40 (7.50%)
    10 / 59 (16.95%)
    5 / 42 (11.90%)
    27 / 261 (10.34%)
         occurrences all number
    2
    2
    0
    4
    1
    0
    1
    5
    10
    1
    4
    11
    6
    32
    Bone pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    3 / 59 (5.08%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    3 / 59 (5.08%)
    0 / 42 (0.00%)
    8 / 261 (3.07%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    2
    0
    3
    0
    10
    Coccydynia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    1 / 59 (1.69%)
    2 / 61 (3.28%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    1
    1
    0
    2
    0
    1
    1
    3
    1
    2
    1
    0
    0
    4
    Groin pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    2 / 261 (0.77%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    0
    2
    0
    2
    0
    0
    0
    2
    Limb discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    2 / 59 (3.39%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    4 / 261 (1.53%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    2
    2
    1
    0
    1
    0
    4
    Muscular weakness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    3 / 40 (7.50%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    10 / 261 (3.83%)
         occurrences all number
    1
    1
    1
    3
    1
    0
    1
    4
    1
    4
    3
    1
    2
    11
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    2 / 40 (5.00%)
    2 / 59 (3.39%)
    2 / 42 (4.76%)
    8 / 261 (3.07%)
         occurrences all number
    4
    0
    0
    4
    0
    0
    0
    4
    0
    2
    2
    2
    2
    8
    Musculoskeletal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    2 / 11 (18.18%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    5 / 59 (8.47%)
    1 / 61 (1.64%)
    1 / 40 (2.50%)
    9 / 59 (15.25%)
    3 / 42 (7.14%)
    19 / 261 (7.28%)
         occurrences all number
    0
    1
    2
    3
    0
    1
    1
    4
    7
    1
    1
    13
    3
    25
    Myalgia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
    2 / 16 (12.50%)
    5 / 58 (8.62%)
    4 / 59 (6.78%)
    4 / 61 (6.56%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    3 / 42 (7.14%)
    13 / 261 (4.98%)
         occurrences all number
    1
    2
    0
    3
    2
    0
    2
    5
    5
    5
    1
    1
    3
    15
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    1 / 40 (2.50%)
    3 / 59 (5.08%)
    4 / 42 (9.52%)
    10 / 261 (3.83%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    0
    2
    0
    2
    1
    3
    4
    10
    Osteoarthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    2 / 11 (18.18%)
    4 / 42 (9.52%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
    2 / 16 (12.50%)
    6 / 58 (10.34%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    3 / 40 (7.50%)
    4 / 59 (6.78%)
    0 / 42 (0.00%)
    12 / 261 (4.60%)
         occurrences all number
    0
    2
    2
    4
    1
    2
    3
    7
    1
    4
    3
    5
    0
    13
    Pathological fracture
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    1
    1
    Acute sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    2
    0
    0
    0
    2
    Bacteraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    0 / 58 (0.00%)
    4 / 59 (6.78%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    6 / 261 (2.30%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    4
    0
    0
    1
    1
    6
    Laryngitis bacterial
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    2 / 59 (3.39%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    2 / 42 (4.76%)
    6 / 261 (2.30%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    3
    0
    0
    2
    3
    8
    Oral candidiasis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    3 / 58 (5.17%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    3 / 261 (1.15%)
         occurrences all number
    1
    1
    0
    2
    1
    0
    1
    3
    0
    2
    0
    1
    1
    4
    Otitis media
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Peritonitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 11 (0.00%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    3 / 58 (5.17%)
    3 / 59 (5.08%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    3 / 59 (5.08%)
    3 / 42 (7.14%)
    10 / 261 (3.83%)
         occurrences all number
    1
    2
    0
    3
    0
    0
    0
    3
    4
    1
    0
    4
    3
    12
    Postoperative wound infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    1 / 42 (2.38%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    1
    2
    0
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    3 / 59 (5.08%)
    8 / 61 (13.11%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    13 / 261 (4.98%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    3
    9
    0
    2
    0
    14
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 15 (20.00%)
    0 / 11 (0.00%)
    4 / 42 (9.52%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    4 / 58 (6.90%)
    2 / 59 (3.39%)
    2 / 61 (3.28%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    0 / 42 (0.00%)
    7 / 261 (2.68%)
         occurrences all number
    3
    3
    0
    6
    0
    0
    0
    6
    2
    2
    2
    4
    0
    10
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    1
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 15 (6.67%)
    3 / 11 (27.27%)
    9 / 42 (21.43%)
    2 / 6 (33.33%)
    2 / 10 (20.00%)
    4 / 16 (25.00%)
    13 / 58 (22.41%)
    18 / 59 (30.51%)
    13 / 61 (21.31%)
    7 / 40 (17.50%)
    17 / 59 (28.81%)
    5 / 42 (11.90%)
    60 / 261 (22.99%)
         occurrences all number
    5
    1
    3
    9
    2
    2
    4
    13
    19
    13
    7
    23
    6
    68
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    2 / 6 (33.33%)
    0 / 10 (0.00%)
    2 / 16 (12.50%)
    5 / 58 (8.62%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    2 / 261 (0.77%)
         occurrences all number
    0
    2
    1
    3
    2
    0
    2
    5
    0
    0
    0
    1
    1
    2
    Diabetes mellitus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    1 / 61 (1.64%)
    0 / 40 (0.00%)
    1 / 59 (1.69%)
    0 / 42 (0.00%)
    3 / 261 (1.15%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    1
    1
    0
    2
    0
    4
    Hypercalcaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    2 / 11 (18.18%)
    3 / 42 (7.14%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    4 / 59 (6.78%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    2 / 59 (3.39%)
    3 / 42 (7.14%)
    9 / 261 (3.45%)
         occurrences all number
    0
    3
    3
    6
    1
    0
    1
    7
    4
    0
    0
    3
    5
    12
    Hyperglycaemia
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    4 / 58 (6.90%)
    1 / 59 (1.69%)
    4 / 61 (6.56%)
    1 / 40 (2.50%)
    3 / 59 (5.08%)
    2 / 42 (4.76%)
    11 / 261 (4.21%)
         occurrences all number
    9
    0
    1
    10
    0
    0
    0
    10
    1
    6
    2
    4
    3
    16
    Hyperkalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 42 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    1 / 58 (1.72%)
    1 / 59 (1.69%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    1 / 42 (2.38%)
    4 / 261 (1.53%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    1
    0
    1
    2
    1
    5
    Hypernatraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    1 / 261 (0.38%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    1
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    3 / 59 (5.08%)
    2 / 61 (3.28%)
    3 / 40 (7.50%)
    4 / 59 (6.78%)
    2 / 42 (4.76%)
    14 / 261 (5.36%)
         occurrences all number
    3
    1
    0
    4
    0
    0
    0
    4
    9
    3
    3
    9
    2
    26
    Hypocalcaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 11 (9.09%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    1 / 40 (2.50%)
    2 / 59 (3.39%)
    5 / 42 (11.90%)
    8 / 261 (3.07%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    0
    2
    0
    0
    1
    3
    6
    10
    Hypoglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    2 / 42 (4.76%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    2 / 58 (3.45%)
    0 / 59 (0.00%)
    0 / 61 (0.00%)
    0 / 40 (0.00%)
    0 / 59 (0.00%)
    0 / 42 (0.00%)
    0 / 261 (0.00%)
         occurrences all number
    1
    2
    0
    3
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    4 / 42 (9.52%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
    5 / 58 (8.62%)
    2 / 59 (3.39%)
    3 / 61 (4.92%)
    2 / 40 (5.00%)
    6 / 59 (10.17%)
    4 / 42 (9.52%)
    17 / 261 (6.51%)
         occurrences all number
    3
    3
    1
    7
    1
    0
    1
    8
    4
    3
    3
    6
    11
    27
    Hypomagnesaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    1 / 42 (2.38%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
    1 / 58 (1.72%)
    0 / 59 (0.00%)
    2 / 61 (3.28%)
    2 / 40 (5.00%)
    3 / 59 (5.08%)
    3 / 42 (7.14%)
    10 / 261 (3.83%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    2
    3
    5
    4
    14
    Hyponatraemia
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 15 (20.00%)
    1 / 11 (9.09%)
    6 / 42 (14.29%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    7 / 58 (12.07%)
    2 / 59 (3.39%)
    3 / 61 (4.92%)
    4 / 40 (10.00%)
    2 / 59 (3.39%)
    3 / 42 (7.14%)
    14 / 261 (5.36%)
         occurrences all number
    4
    3
    1
    8
    0
    1
    1
    9
    2
    3
    4
    2
    3
    14
    Hypophosphataemia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    1 / 11 (9.09%)
    3 / 42 (7.14%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
    1 / 16 (6.25%)
    4 / 58 (6.90%)
    3 / 59 (5.08%)
    4 / 61 (6.56%)
    1 / 40 (2.50%)
    1 / 59 (1.69%)
    2 / 42 (4.76%)
    11 / 261 (4.21%)
         occurrences all number
    0
    3
    2
    5
    0
    2
    2
    7
    15
    7
    1
    2
    2
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2015
    Reduced the starting dose of spartalizumab to 1 mg/kg administered once every two weeks, as requested by a regulatory authority.
    15 Jun 2015
    Phase II part of the study was to focus specifically on subjects with NSCLC, melanoma and TNBC; the planned expansion groups for subjects with gastric and esophageal cancer, colorectal cancer and anal cancer were removed. Removal of the gastric/esophageal, colorectal and anal cancer groups also affects the role of the PD-L1 biomarker, which was an inclusion criterion for these subjects. No molecular screening for PD-L1 was performed to select subjects however PD-L1 expression was assessed retrospectively for all subjects. At the time of RP2D/MTD determination, the amount of efficacy data collected would be limited. To provide greater confidence in choosing the most appropriate dose for further development, the study design was updated to allow testing of two doses of spartalizumab in one disease indication during the Phase II part. In addition, collection of a sample for cytokine assessment (IL-6 and IFN-γ) was added for all subjects at Screening. The wording in prohibited concomitant therapy related to the use of systemic steroid therapy during the course of study was adjusted in order to provide more flexibility for subjects who would need such therapy for treatment of acute conditions. In order to align the collection and analysis of pharmacodynamic biomarkers with preclinical evidence on the timing of immune response in tumor after therapy with PD-1 blocking antibodies, the collection of the on-treatment new tumor biopsy sample was moved from C2D1 (i.e. between C2D1 and C2D15) to C3D1 (i.e. between C3D1 and C3D15).
    19 Sep 2015
    Restricting subjects with NSCLC to no more than one prior platinum-based doublet chemotherapy regimen, with the exception of subjects with ALK or EGFR-positive disease who were treated with a relevant tyrosine kinase inhibitor and a platinum-based doublet chemotherapy regimen. For subjects with melanoma, all subjects must have developed progressive disease after at least one systemic treatment regimen (for those with BRAF-wild type disease) or one systemic treatment regimen and a BRAF inhibitor (for those with BRAF-mutant disease). No disease-specific limitations were required for subjects with TNBC. Subjects who had previously received a PD-1 or PD-L1 checkpoint inhibitor were excluded from participating; those who had previously received other anticancer immunotherapies such as CTLA-4-directed therapy were eligible. Allowed the testing of a fixed/flat dose of spartalizumab in the phase II part of the study. The use of a fixed/flat dose would reduce the risk of dosing errors and reduce drug product wastage. The requirement that subjects have disease that could be biopsied and be willing to undergo biopsy during the Phase II part of the study was adjusted to allow exceptions after documented discussion with Novartis. This amendment also introduced the possibility to stop the collection of biopsies, once a sufficient number of paired biopsies had been collected. Allowed the collection of tumor tissue upon the development of acquired resistance to treatment. Based on preliminary PK data and the possibility of delayed appearance of immune-related adverse events, the safety follow-up period was extended to 90 days after the last dose of study treatment. Exclusion criteria were updated to exclude sexually active male subjects who were not willing to use a condom during the study.
    13 May 2016
    n the Phase II part. This regimen was to be tested in addition to the RP2D of 400 mg Q4W. Subjects with melanoma were no longer required to have received systemic therapy prior to being eligible for treatment with spartalizumab. All subjects with BRAF V600 mutant melanoma must have received a BRAF inhibitor. Subjects with NSCLC could have received no more than one prior platinum-based doublet therapy. For NSCLC, the subjects with EGFR mutation-positive disease were excluded as the published data suggest these subjects receive limited benefit from treatment with single agent PD-1 inhibitors (Borghaei et al 2015). Subjects with ALK translocation-positive NSCLC were eligible, as the currently available published dataset for these subjects treated with PD-1 inhibitors is limited. A group of subjects was added with anaplastic thyroid cancer in the Phase II part. This was an exploratory group for a type of cancer without effective treatment options. Exclusion criteria was updated to exclude subjects with electrolyte abnormalities > CTCAE grade 2 and a washout period of 4 weeks was required only for live vaccines and to exclude subjects who may not comply with the study for nonmedical reasons. The ECOG performance inclusion criterion was changed to ≤ 1. The inclusion criteria of the Phase II part of the study required that the status was known for EGFR (and ALK if EGFR mutation-negative) for subjects with NSCLC, and for BRAF V600 for subjects with melanoma; included the determination of molecular parameters (EGFR, ALK, or BRAF V600 mutational status) at molecular pre-screening by a local laboratory, or by a Novartis-designated laboratory if a local laboratory test was not feasible, for subjects with a tumor of unknown status. Prohibited concomitant therapy section was updated to allow localized radiotherapy for non-target lesions
    30 Sep 2016
    Increased the duration of contraception and safety follow-up periods post spartalizumab treatment from 90 days to 150 days, using five times the upper limit of the half-life of 23 days and an added safety margin. These changes were related to an Urgent Safety Measure communicated on 08-Jun-2016 to all Investigators. With the available PK data obtained from this study an exploratory population PK (PopPK) analysis showed that the T1/2 of spartalizumab in man is 20 [17, 23] days (mean [90% CI]). Many subjects were most likely start a new antineoplastic therapy during the 150 day safety follow-up. Therefore, after the start of a new antineoplastic therapy during the safety follow-up, only AEs and SAEs suspected to be related to spartalizumab were collected in order to focus on the collection of information relevant to spartalizumab; and concomitant medications were recorded until the 30-day safety follow-up or the start of new antineoplastic, whatever occurred first. This amendment also includes new blood samples for PK and PD assays to assess RO in blood and pathway modulation in peripheral blood by analysis of circulating humoral factors and cell based markers (e.g. RNA profiling and FACS analysis of PBMC). RO samples were collected at Day1 of Cycles 1, 3 and 6 and at EoT. In addition RO and PK samples were collected 150 days after last dose. RO samples were collected from all subjects. For pharmacodynamics plasma and PBMCs were collected at Cycle 1 Day 1, Cycle 1 Day15, Cycle 3 Day 1 and 150 days after last dose.
    27 Jul 2017
    Removed the requirement for progression on prior therapy for subjects with ATC; subjects were no longer required to have received therapy prior to being eligible for treatment with spartalizumab. Outcomes for subjects with this disease are dismal with a median life expectancy after diagnosis of less than six months. Given the poor outcome after standard therapy current NCCN treatment guidelines recommend that all subjects be considered for clinical studies. The inclusion criteria was revised in this amendment to allow treatment earlier in the disease course. Specific changes to inclusion criterion #4 for subjects with ATC included: - Subjects were not required to have received or progressed on a prior therapy. - Subjects must not be at short term risk for life threatening complications (such as airway compromise or bleeding from locoregional or metastatic disease). - Chemoradiation and/or surgery was to be considered prior to study entry for those subjects with locally advanced Mutations affecting BRAF occur in approximately 11% - 27% of subjects with ATC. To facilitate a more complete understanding of the subject population benefiting from treatment with spartalizumab, tumor samples were to be tested to determine BRAF V600 mutational status. Knowledge of the BRAF mutation status was not required for study entry. ECG collection was needed only at Screening and as clinically indicated. Prohibited concomitant therapy was modified to better align with medical practice in immuno-oncology. Prohibited concomitant therapy was modified to better align with medical practice in immuno-oncology. Separate primary analyses and indication-specific complete clinical study reports could be provided for this study. Therefore, the protocol was amended to allow separate primary analyses.
    16 Jul 2018
    Incorporated health authority-requested language requiring study treatment discontinuation in the event of Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). Revised to align with recently published guidelines on the clinical management of suspected immune-related toxicities. Removed the use of condom for male study participants receiving spartalizumab. Receptor occupancy and pharmacodynamic (PBMCs and cytokines) samples for markers were no longer to be collected post first primary CSR data cut-off. Language was updated for irRC assessment to clarify criteria for new measurable lesions and irRC response in case of only non-measurable disease at baseline. Removed the reporting of total dose per cycle from statistical section. More details and clarifications were added for reporting other secondary efficacy objectives. Modifications were made to follow Novartis analysis standards safety.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/#/
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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